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Cannabinoids Inhibit Insulin Receptor Signaling in Pancreatic β-Cells.

Authors :
Wook Kim
Doyle, Máire E.
Zhuo Liu
Qizong Lao
Yu-Kyong Shin
Carlson, Olga D.
Hee Seung Kim
Thomas, Sam
Napora, Joshua K.
Eun Kyung Lee
Moaddel, Ruin
Yan Wang
Maudsley, Stuart
Martin, Bronwen
Kulkarni, Rohit N.
Egan, Josephine M.
Source :
Diabetes. Apr2011, Vol. 60 Issue 4, p1198-1209. 12p. 5 Color Photographs, 1 Black and White Photograph, 2 Graphs.
Publication Year :
2011

Abstract

OBJECTIVE--Optimal glucose homeostasis requires exquisitely precise adaptation of the number of insulin-secreting β-cells in the islets of Langerhans. Insulin itself positively regulates β-cell proliferation in an autocrine manner through the insulin receptor (IR) signaling pathway. It is now coming to light that cannabinoid 1 receptor (CBIR) agonism/antagonism influences insulin action in insulin-sensitive tissues. However, the cells on which the CBIRs are expressed and their function in islets have not been firmly established. We undertook the current study to investigate if intraislet endogenous cannabinoids (ECs) regulate β-cell proliferation and if they influence insulin action. RESEARCH DESIGN AND METHODS--We measured EC production in isolated human and mouse islets and β-cell line in response to glucose and KC1. We evaluated human and mouse islets, several β-cell lines, and CB1R-null (CB1R-/-) mice for the presence of a fully functioning EC system. We investigated if ECs influence β-cell physiology through regulating insulin action and demonstrated the therapeutic potential of manipulation of the EC system in diabetic (db/db) mice. RESULTS--ECs are generated within β-cells, which also express CBIRs that are fully functioning when activated by ligands. Genetic and pharmacologic blockade of CBIR results in enhanced IR signaling through the insulin receptor substrate 2-AKT pathway in β-cells and leads to increased β-cell proliferation and mass. CBIR antagonism in db/db mice results in reduced blood glucose and increased β-cell proliferation and mass, coupled with enhanced IR signaling in β-cells. Furthermore, CBIR activation impedes insulin-stimulated IR autophosphorylation on β-cells in a Gαi-dependent manner. CONCLUSIONS--These findings provide direct evidence for a functional interaction between CB1R and IR signaling involved in the regulation of β-cell proliferation and will serve as a basis for developing new therapeutic interventions to enhance β-cell function and proliferation in diabetes. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00121797
Volume :
60
Issue :
4
Database :
Academic Search Index
Journal :
Diabetes
Publication Type :
Academic Journal
Accession number :
60678757
Full Text :
https://doi.org/10.2337/db10-1550